Process for iohexol manufacture

ABSTRACT

The present invention relates to a process for the manufacture of iohexol, 5-[N-(2,3-dihydroxypropyl)-acetamido]-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophtalamide by selecting a solvent comprising a C 1 -C 5 -monoalkylether of a C 3 -C 10  alkylene-glycol.

The present invention relates to a process for the manufacture ofiohexol,5-[N-(2,3-dihydroxypropyl)-acetamido]-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophtalamide.

Iohexol is the non-proprietory name of the chemical drug substance of anon-ionic iodinated X-ray contrast agent marketed under the trade nameOMNIPAQUE®. OMNIPAQUE® is one of the most used agents in diagnosticX-ray procedures.

The manufacture of such non-ionic contrast agents involves theproduction of the chemical drug substance (referred to as primaryproduction) followed by formulation into the drug product (referred toas secondary production). Primary production of iohexol involves amultistep chemical synthesis and a thorough purification stage. For acommercial drug product it is important for the primary production to beefficient and economical and to provide a drug substance fulfilling thespecifications.

The final step in the synthesis of iohexol is a N-alkylation step inwhich 5-(acetamido)-N,N′-bis(2,3-dihydroxypropyl)-2,4,6triiodoisophtalamide (hereinafter 5-Acetamide) is reacted in the liquidphase with an alkylating agent to introduce the 2,3-dihydroxypropylgroup at the nitrogen of the 5-acetamido group. Following this reaction,iohexol is isolated from the reaction mixture and purified bycrystallisation and treatment with ion exchange resins.

The manufacture of iohexol is disclosed for example in U.S. Pat. No.4,250,113 which is hereby incorporated by reference. In the last step ofthe multistep chemical synthesis crude iohexol is obtained from thereaction between 5-Acetamide and 1-chloro-2,3-propandiol at ambienttemperature in propylene glycol and in the presence of sodium methoxide.The solvent is then evaporated and crude iohexol is obtained. The crudeproduct is evaporated to dryness and recrystallised twice from butanol.

Several suggestions to improve the N-alkylation and the purificationsteps have been published. WO-A-98/08804 discloses the use of2-methoxy-ethanol and optionally isopropanol both in the alkylation stepof 5-Acetamide and in the purification of crude iohexol. WO-A-02/083623discloses the purification of crude iohexol using 1-methoxy-2-propanolas the solvent optionally in a mixture with other solvents.

The N-alkylation step where 5-Acetamide in solution is reacted with analkylation agent such as e.g. 1-chloro-2,3-propandiol to introduce the2,3-dihydroxypropyl group at the nitrogen of the 5-acetamido group isillustrated in Scheme 1:

The N-alkylation step is challenging because O-alkylated by-products canalso be formed when the alkylation occurs at the oxygen atoms of thehydroxy groups. It is therefore a desire to limit the formation of theseO-alkylated by-products and thereby to limit their presence in the finalpurified iohexol. The upper limit for values for O-alkylated by-productsin the end product is fixed by the European Pharmacopea to 0.6% (HPLC byarea).

The O-alkylated by-products are removed to the degree desired ornecessary by recrystallisation steps. Further unidentified by-productsalso referred to as impurities are also formed during the alkylationreaction and must be reduced to a tolerable level. In addition thesolvents used should be easily available, be environmentally friendlyand be of low toxicity.

There is therefore a need to identify a solvent that can be used in theN-alkylation reaction and that fulfil the desiderata mentioned above. Itis further desired to improve the overall process including theN-alkylation step and the purification step in the manufacture ofiohexol. If the crude product obtained by the N-alkylation step is to bere-crystallised from a solvent that is different from the solvent usedin the N-alkylation step, then the reaction solvent must first beremoved e.g. by evaporation to dryness. It is known from crystallisationtheory and experience that even small quantities of residual solventsfrom previous steps may cause a crystallisation process to get out ofcontrol due to changes in its supersaturation conditions, and thoroughremoval of the reaction solvent is an important step. Solvent removal isan energy consuming operation which also risks degradation of theproduct due to exposure to elevated temperature.

The present invention improves the manufacture of iohexol meeting theneeds discussed above.

It has now surprisingly been found that the use of a solvent comprisinga C₁-C₅-monoalkylether of a C₃-C₁₀ alkylene-glycol in the N-alkylationof 5-Acetamide will give crude iohexol in almost quantitative yield.

It has further been found that by using a solvent comprising aC₁-C₅-monoalkylether of a C₃-C₁₀ alkylene-glycol both in the alkylationof 5-Acetamide and for the subsequent crystallisation of the resultingiohexol further improves the economy of the process and the overallyield and purity of the resulting iohexol product.

The specific characteristics of the invention will be evident from thepatent claims.

In a first embodiment the invention provides a process for theproduction of iohexol comprising reacting 5-Acetamide with a2,3-dihydroxypropylating agent in the presence of a base and of asolvent, the solvent comprising the C₁-C₅-monoalkylether of a C₃-C₁₀alkylene-glycol. This process is illustrated in scheme 1 where thesolvent comprises the C₁-C₅-monoalkylether of a C₃-C₁₀ alkylene-glycol.

In a preferred aspect of the invention the C₁-C₅-monoalkylether of aC₃-C₁₀ alkylene-glycol is mixed with other solvents thus forming asolvent mixture. Such co-solvents are C₁-C₄ alkanols or water ormixtures of the alkanols and water. The co-solvents when used mayconstitute from about 10 volume % to about 60 volume % of the solventmixture. A solvent consisting of the C₁-C₅-monoalkylether of a C₃-C₁₀alkylene-glycol and a C₁-C₄ alkanol is preferred, and it is particularlypreferred to use a solvent mixture where the C₁-C₄ alkanol is present inan amount of about 30 volume %. When water is used together with theC₁-C₅-monoalkylether of a C₃-C₁₀ alkylene-glycol the water content ofthe solvent mixture should be up to 20 volume % and preferably about 10volume %.

The preferred C₁-C₅-monoalkylether of a C₃-C₁₀ alkylene-glycol is1-methoxy-2-propanol. Preferably 40-90 volume % of 1-methoxy-2-propanolis mixed with other solvents as outlined above. In a specificallypreferred aspect a solvent mixture of 1-methoxy-2-propanol and up to 40volume % methanol is used, with about 30 volume % methanol being mostpreferred. Alternatively a solvent mixture of 1-methoxy-2-propanol andup to 20 volume % water is used, with about 10 volume % of water beingmost preferred.

The solvents used in the process according to the invention arepreferably used in an amount of 0.5-5 ml per gram of 5-Acetamide, morepreferred 0.7 to 3 ml per gram of 5-Acetamide and with 0.9-1.0 ml pergram of 5-Acetamide being the most preferred concentration.

The 2,3-dihydroxypropylating agent used in the N-alkylation reaction isany 2,3-dihydroxypropanol having a leaving group attached in the1-position. 1-halo-2,3-propanediols are preferred with1-chloro-2,3-propanediol being the most preferred2,3-dihydroxypropylating agent. Alternatively, glycidol may be used asthe 2,3-dihydroxypropylation agent. A molar excess of2,3-dihydroxypropylation agent is preferably used e.g. 1.2-1.4 moles permole of 5-Acetamide.

The N-alkylation step takes place in the presence of a base. The baseused in the N-alkylation process according to the invention must besoluble in the reaction solvent. Alkali metal hydroxide is the preferredbase and sodium hydroxide being most preferred.

The N-alkylation step is preferably effected at a temperature between15-50° C., with 23-25° C. being the most preferred process temperature.

The N-alkylation step will be allowed to proceed for several hours witha preferred reaction time of 12 to 48 hours and particularly preferredfrom 18 to 30 hours. The reaction may be terminated by quenching with anacid. Inorganic or organic acids may be used and inorganic acids such asHCl are preferred. The reaction may be monitored, e.g. by HPLC, todetermine the appropriate stage at which quenching should take place.

Following termination of the reaction, the crude iohexol reactionproduct may be separated from the solvent e.g. by cooling and/or solventevaporation. The evaporation should preferably be performed underreduced pressure. Usually most of the solvent from the N-alkylation stepis distilled off, to produce a concentrated solution from which iohexolis further separated. The separation of the solvent is usually performedafter the reduction of the salt content of the reaction mixture isperformed.

After quenching the salt produced in the N-alkylation step is optionallyreduced before the isolation of iohexol or further purification isstarted. The optionally reduction of the salt content is done withoutthe need of removal of the solvents from the N-alkylation step. The bulkamount of salt can be removed by precipitation and filtering followed,if necessary, by treatment with a cationic ion exchange resin and ananionic ion exchange resin. The resulting iohexol in solution may beisolated by crystallisation directly from the solvents by evaporation ofthe solvents preferably by distillation under reduced pressure oriohexol may be further purified. By using the solvent or solvent mixtureof the invention it is possible to obtain iohexol with a purity thatsatisfies the criteria of the European Pharmacopea of 0.6% (or less) ofO-alkylated by-products without further recrystallisation procedures. Ina final step iohexol is usually washed with isopropanol.

Although iohexol may be obtained directly from the N-alkylation reactionin a purity sufficient to satisfy the criteria of the EuropeanPharmacopeia as outlined above, it is frequently desirable or necessaryto further purify the product from the N-alkylation. Hence, in a furtheraspect of the invention the iohexol from the N-alkylation stepoptionally where the salt content is reduced (denoted “crude iohexol”)is further purified using a solvent comprising a C₁-C₅-monoalkylether ofa C₃-C₁₀ alkylene-glycol. In a preferred aspect the sameC₁-C₅-monoalkylether of a C₃-C₁₀ alkylene-glycol as is used in theN-alkylation step is also used in the purification step and optionallytogether with a C₁-C₄ alkanol as co-solvent.

The solvent amounts are adjusted to 1.5-8 ml of the C₁-C₅-monoalkyletherof a C₃-C₁₀ alkylene-glycol/g iohexol and 0-1 ml of the C₁-C₄ alkanol/giohexol and the water content is reduced to 0.001-0.3 ml water/giohexol. 1-methoxy-2-propanol is preferably used, however a solventmixture such as a mixture of 1-methoxy-2-propanol with methanol may alsobe used in the concentrations of 1.5-8 ml preferably 2-6 ml of1-methoxy-2-propanol/g iohexol, 0-1 ml methanol/g iohexol and a watercontent of 0.001-0.3 ml water/g iohexol.

The purification is preferably performed by the crystallisation ofiohexol from the solvent or solvent mixture and separation of thecrystals from the solvent. One crystallisation is usually sufficient toprovide iohexol of a very good quality exceeding the criteria of theEuropean Pharmacopeia. Starting with the solution of crude iohexol fromthe N-alkylation process and where excess salt has been removed wherenecessary by precipitation and/or ion exchange procedures, excess wateris removed preferably by azeotropic distillation. The solvent amountsare adjusted during the distillation to satisfy the limits given aboveand the solution is seeded with iohexol crystals. The seeded solution isstirred with reflux and the volume is adjusted by distillation underreduced pressure. The solution is cooled under stirring and thecrystalline iohexol is filtered off. The crystalline product ispreferably washed with isopropanol and dried.

The purification process is preferably effected at a temperature range50-130° C. with a temperature range of 60-120° being most preferred. Thepurification of iohexol according to the invention is preferablyeffected over a time of approximately 4 hours to 2 days.

An important aspect of the improved quality obtained with the processaccording to the present invention and in particular when theN-alkylation step is followed by a further purification step is theability to reduce the amount of O-alkylated by-products. The O-alkylatedcompounds are impurities that are difficult to remove in thepurification process. The European Pharmacopea iohexol specification ofan upper limit of 0.6% (by HPLC area) is one of the limiting factors inthe process for obtaining a final product of necessary quality. It istherefore of critical importance to avoid formation of such O-alkylatedby-products as much as possible in the N-alkylation process. Further,the enhanced purification effect by using the specific solvents of theinvention makes it possible to obtaining an average of approximately0.45% O-alkylated by-products instead of 0.51 to 0.55% O-alkylatedby-products as was obtained in WO 98/08804 from an average crude iohexolprocess stream. This reduction is of great importance. The ability toobtain a final iohexol product with an amount of O-alkylated by-productswell beyond the limits of the European Pharmacopea provide the producerwith the ability to optimise other important process parameters andthereby increase e.g. the yield and to accept some batch variation andstill obtain a product that satisfies the criteria for iohexol of theEuropean Pharmacopea.

The invention will hereinafter be illustrated by the non-limitingexamples. All percent are in HPLC area % when not stated otherwise.

EXAMPLE 1 Synthesis of iohexol in 1-methoxy-2-propanol/methanol

1-methoxy-2-propanol (44 ml), methanol (19 ml) and sodium hydroxide(4.87 g) was added to a jacketed glass reactor and stirred for about 15minutes at 25° C. 5-Acetamide (70 g) was added to the reactor, and themixture stirred overnight at 45° C., before it was allowed to cool to25° C. 1-chloro-2,3-propanediol (12.43 g) was added to the solution.After 1.5 hours, more 1-chloro-2,3-propanediol (0.83 g) was added, andthe reaction was allowed to proceed for 24 hours. HPLC analysis(water/acetonitrile) of the reaction mixture gave the following results:Iohexol 98.1% 5-Acetamide 1.17% O-alkylated substances 0.58% Otherimpurities  0.1%

EXAMPLE 2 Synthesis of iohexol in 1-methoxy-2-propanol/water

1-methoxy-2-propanol (63 ml), water (7 ml) and sodium hydroxide (4.50 g)was added to a jacketed glass reactor and stirred for about 15 minutesat 25° C. 5-Acetamide (70 9) was added to the reactor, and the mixturestirred overnight at 45° C., before it was allowed to cool to 35° C.1-chloro-2,3-propanediol (11.39 g) was added to the solution. After 3hours, more 1-chloro-2,3-propanediol (0.83 g) was added, and thereaction was allowed to proceed for 24 hours. HPLC analysis(water/acetonitrile) of the reaction mixture gave the following results:Iohexol 98.3% 5-Acetamide 0.68% O-alkylated substances 0.81% Otherimpurities  0.3%

EXAMPLE 3 Alkylation and crystallisation in solutions containing1-methoxy-2-propanol

1-methoxy-2-propanol (63 L), methanol (27 L) and sodium hydroxide (6.96kg) was added to a 500 L-reactor and stirred until all solids weredissolved and the temperature was below 30° C. 5-Acetamide (100 kg) wasadded to the reactor, and the mixture stirred overnight at 45° C. beforeit was allowed to cool to 25° C. 1-chloro-2,3propanediol (16.76 kg) wasadded to the clear solution. After 1.5 hours, more1-chloro-2,3-propanediol (1.18 kg) was added, and the reaction wasallowed to proceed for 30 hours. HPLC analysis (water/acetonitrile) ofthe reaction mixture gave the following results: Iohexol 97.9%5-Acetamide  0.9% O-alkylated substances 0.83% Other impurities  0.4%

The reaction was stopped by addition of hydrochloric acid (650 ml), andthe reaction mixture diluted with a mixture of 1-methoxy-2-propanol (53L) and methanol (13 L). The mixture was filtered, and the salts on thefilter washed with methanol (3×10 L). The combined filtrate and wash wasdiluted with water (22 L) and treated with cationic ion exchange resin(AMB 200C, 80 L) and anionic ion exchange resin (IRA 67, 80 L) to a saltcontent of 0.006 w/w %. The solution was filtered, and the ion exchangeresins washed in several stages with a mixture of water (160 L) andmethanol (85 L). The combined filtrate and wash was concentrated underreduced pressure to a volume of 155 L. One half of this was takenfurther to crystallisation as described below.

Water was removed from the solution by azeotropic distillation. Thevolume was held at a constant level by replacing the distillate by1-methoxy-2-propanol (80 L). At water content of 0.16 L/kg iohexol,further 1-methoxy-2-propanol (159 L) was added, and the solution seededwith iohexol crystals (0.26 kg). After stirring at reflux overnight, thevolume of the solution was reduced by 42 L by distillation under reducedpressure (300-600 mbar). The temperature was set to 90° C., which washeld for 3 hours before cooling to 60° C. over 3 hours. Thecrystallisation mixture was stirred overnight at 60° C., filtered andwashed with isopropanol (90 L, 6 portions). The yield was 48.4 kg (asdry powder), corresponding to 88-weight % corrected for seeding materialand samples. HPLC analysis (water/acetonitrile) of the crystals gave thefollowing results: Iohexol 99.3% 5-Acetamide 0.15% O-alkylatedsubstances 0.45% Other impurities 0.11%

1. A process for the production of iohexol comprising alkylating5-(acetamido)-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophtalamidewith a 2,3-dihydroxypropylating agent in the presence of a base and of asolvent which solvent comprises a C₁-C₅-monoalkylether of a C₃-C₁₀alkylene-glycol.
 2. A process as claimed in claim 1 wherein said glycolis 1-methoxy-2-propanol.
 3. A process as claimed in claim 1 furthercomprising one or more co-solvents.
 4. A process as claimed in claim 3wherein said co-solvents comprise C₁-C₄ alkanols, preferably methanol,and/or water.
 5. A process as claimed in claim 3 on wherein said solventcomprises 1-methoxy-2-propanol and 0-40 volume % of methanol.
 6. Aprocess as claimed in claim 3 on wherein said solvent comprises1-methoxy-2-propanol and 0-20 volume % of water.
 7. A process as claimedin claim 1 wherein said solvent is used in an amount of 0.5 to 5 ml,more preferred 0.7 to 3 ml and most preferred 0.9 to 1.0 ml per gram5-Acetamide.
 8. A process as claimed in claim 1 further comprisingpurifying the crude iohexol obtained from the N-alkylation reactionusing a solvent comprising a C₁-C₅-monoalkylether of a C₃-C₁₀alkylene-glycol.
 9. A process as claimed in claim 8 wherein theC₁-C₅-monoalkylether of a C₃-C₁₀ alkylene-glycol is the same glycol asused in the N-alkylation process.
 10. A process as claimed in claim 8wherein in said purification the C₁-C₅-monoalkylether of a C₃-C₁₀alkylene-glycol is 1-methoxy-2-propanol.
 11. A process as claimed inclaim 8 wherein said purification the solvent further comprises one ormore co-solvents.
 12. A process as claimed in claim 11 wherein saidco-solvent comprises C₁-C₄ alkanols and preferably methanol.
 13. Aprocess as claimed in claim 9 wherein the amount of said solvent isadjusted to 1.5 to 8 ml of the C₁-C₅-monoalkylether of a C₃-C₁₀alkylene-glycol/g iohexol, to 0-1 ml C₁-C₄ alkanol/g iohexol, and to0.001-0.3 ml water/g iohexol.
 14. A process as claimed in claim 8wherein the purification is performed by crystallising the iohexol fromsaid solvent and then separating the crystals from said solvent.
 15. Aprocess as claimed in claim 8 wherein the salt content in the reactionmixture of the alkylation reaction is reduced prior to the purificationstep.
 16. A process as claimed in claim 8 wherein the water content inthe reaction mixture of the alkylation reaction is reduced prior to thecrystallisation step preferably by azeotropic distillation.
 17. Aprocess as claimed in claim 8 wherein the crystalline iohexol is washedwith isopropanol and dried.